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Trial registered on ANZCTR


Registration number
ACTRN12620000815965
Ethics application status
Approved
Date submitted
18/06/2020
Date registered
14/08/2020
Date last updated
14/08/2020
Date data sharing statement initially provided
14/08/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase II Trial of Doxycycline with Radiotherapy for Rectal Cancer
Scientific title
A Non-Randomised Comparative Phase II Trial of Doxycycline as a Cancer Stem Cell Inhibitor in Patients Undergoing Short-Course Radiotherapy Followed by Surgical Resection for Rectal Cancer
Secondary ID [1] 300883 0
Nil known
Universal Trial Number (UTN)
U1111-1248-0681
Trial acronym
DOXY-RC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rectal Cancer 317003 0
Condition category
Condition code
Cancer 315166 315166 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Doxycycline is a broad-spectrum antibiotic, which prevents the binding of amino-acyltRNA to the messenger RNA-30S ribosomal subunit, preventing polyribosome formation. It is approved in New Zealand for the treatment of chronic prostatitis, sinusitis, syphilis, pelvic inflammatory disease, malaria, recurrent aphthous ulceration, and acne vulgaris. Doxycycline primarily exerts it's antimicrobial action by bacteriostasis. It also has antinflammatory effects.

Doxycycline will be administered as two 100mg tablets orally each morning, starting two days prior to the first dose of short-course radiotherapy (SCRT), until one day prior to surgery for rectal cancer. Surgery will be performed within three weeks of starting radiotherapy treatment. The duration of doxycycline will be between 12 and 23 days, and will be determined by each participant's individual treatment schedule.

Adherence will be assessed through a combination of a patient diary, and count of the number of tablets remaining in the drug container on the patients admission for rectal cancer surgery.
Intervention code [1] 317297 0
Treatment: Drugs
Comparator / control treatment
Retrospective control participants will be be recruited in a reverse sequential order from records kept by the Waikato District Health Board Radiation Oncology Department, from patients who have undergone short course radiotherapy for rectal cancer between January 2016 and July 2020. Tumour biopsy and surgical specimens will be retrieved for analysis from the Histopathology Laboratory at Waikato District Health Board, where they are stored indefinitely as standard of care. Recruitment of Maori will be prioritised, with a target of 30% control participants.
Control group
Historical

Outcomes
Primary outcome [1] 323428 0
Difference in the mean immunohistochemistry (IHC) H-scores for CD133 in resected tumours between the doxycycline and control groups.
Timepoint [1] 323428 0
Based on rectal cancers surgically resected within 3 weeks of radiotherapy.
Secondary outcome [1] 381913 0
Difference in the mean immunohistochemistry H-scores for ALDH1 in resected tumours between the doxycycline and control groups.
Timepoint [1] 381913 0
Based on rectal cancers surgically resected within 3 weeks of radiotherapy.
Secondary outcome [2] 381914 0
Mean change in immunohistochemistry H scores for CD133 between each patient’s resected tumour and diagnostic biopsy in the doxycycline group compared to the control groups.
Timepoint [2] 381914 0
Based on diagnostic biopsies from which the diagnosis of cancer was made and rectal cancers surgically resected within 3 weeks of radiotherapy.
Secondary outcome [3] 381915 0
Mean change in immunohistochemistry H scores for ALDH1 between each patient’s resected tumour and diagnostic biopsy in the doxycycline group compared to the control groups.
Timepoint [3] 381915 0
Based on diagnostic biopsies from which the diagnosis of cancer was made and rectal cancers surgically resected within 3 weeks of radiotherapy.
Secondary outcome [4] 381916 0
The distribution of cells staining positively for CD133 within each resected tumour (invasive margin, centrally, both).
Timepoint [4] 381916 0
Based on rectal cancers surgically resected within 3 weeks of radiotherapy.
Secondary outcome [5] 381917 0
The predominant intracellular location of CD133 staining in CD133 positive cells within each tumour (cytoplasmic, membranous or nuclear).
Timepoint [5] 381917 0
Based on rectal cancers surgically resected within 3 weeks of radiotherapy.
Secondary outcome [6] 381919 0
The distribution of cells staining positively for ALDH1 within each tumour (invasive margin, centrally, both).
Timepoint [6] 381919 0
Based on rectal cancers surgically resected within 3 weeks of radiotherapy.
Secondary outcome [7] 381920 0
The predominant intracellular location of ALDH1 staining in ALDH1 positive cells (cytoplasmic, membranous or nuclear).
Timepoint [7] 381920 0
Based on rectal cancers surgically resected within 3 weeks of radiotherapy.
Secondary outcome [8] 381921 0
Cancer lymph node involvement will be documented from the histopathology report (lymph node involvement present or absent).
Timepoint [8] 381921 0
Based on rectal cancers surgically resected within 3 weeks of radiotherapy.
Secondary outcome [9] 384743 0
Treatment-emergent adverse events in the doxycycline group classified using CTCAE v5 (Eg. diarrhoea, nausea, rash, photosensitivity reaction).
Timepoint [9] 384743 0
Based on participant diaries completed daily starting one day prior to doxycycline treatment, and continued until the day before admission for surgery.
Secondary outcome [10] 384744 0
Adherence with doxycycline dosing as proportion of intended dose taken.
Timepoint [10] 384744 0
Based on participant diaries and a count of pills remaining on the day of admission for surgery,
Secondary outcome [11] 384745 0
Completeness of wound healing (yes/no).
Timepoint [11] 384745 0
Based on assessment at the first surgical follow clinic approximately 3 weeks post-operatively.

Eligibility
Key inclusion criteria
1. Pathologically-confirmed rectal adenocarcinoma.
2. Magnetic resonance imaging (MRI) stage T3-4, and/or N1-2, or full thickness low T2 lesions where R0 resectability is in doubt.
3. ECOG performance status of 0–2.
4. Adequate liver function on blood tests taken within four weeks of commencing doxycycline (e.g. ALT/AST <3 x ULN, bilirubin <1.5 x ULN).
5. Surgery planned to occur within 3 weeks of starting SCRT.
6. Willing and able to comply with all trial requirements, including treatment and timing and/or nature of required assessments.
7. Signed, written informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Received chemotherapy for their rectal cancer prior to SCRT;
2. Allergy to doxycycline.
3. Currently taking medications with which doxycycline is known to have clinically-significant drug-drug interactions including systemic retinoids, oral antacids, oral iron or calcium, carbamazepine, phenytoin, enzalutamide, lithium, ergotamine, diuretics, oral contraceptive pill, quinapril, rifampicin, warfarin, methotrexate, st johns wort, ciclosporin.
4. Myasthenia gravis;
5. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.
6. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.
7. Prior high dose radiotherapy to the pelvis.
8. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal,
infertile, or use a reliable means of contraception. Women of childbearing potential must
have a negative pregnancy test done within 7 days prior to starting treatment. Men must have been surgically sterilised or use a barrier method of contraception.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary endpoint is the IHC H-score for CD133 expression the resected specimens, using the mean of H-scores. For this study, 19 patients per group gives 90% power (2a =0.05) to detect a difference of 0.8 SD between the mean change in CD133 H-score between patients in the doxycycline and control groups. An additional patient in each arm has been included to allow for failure of IHC staining. Analysis will be based on an intention-to-treat evaluation. The primary endpoint will be tested for normality, then analysed to determine any statistical significance between the control and doxycycline
groups, using an independent t-test or non-parametric equivalent (Mann-Whitney U). Subgroups will be analysed using ANOVA or non-parametric equivalent (Kruskal-Wallis). Analysis of proportions in secondary endpoints will be conducted using chi-square or Fisher exact tests. AE in the doxycycline group will be tabulated. Spearman rank correlation will be used to evaluate the association between CD133 and ALDH1 expression scores.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
17/08/2020
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment outside Australia
Country [1] 22479 0
New Zealand
State/province [1] 22479 0
Waikato

Funding & Sponsors
Funding source category [1] 305334 0
Charities/Societies/Foundations
Name [1] 305334 0
Waikato Medical Research Foundation
Country [1] 305334 0
New Zealand
Primary sponsor type
Individual
Name
Dr Natalie Briggs
Address
Waikato Cancer and Blood Research Trial Unit
Pembroke Street
Hamilton West
Hamilton 3204
Country
New Zealand
Secondary sponsor category [1] 305703 0
Individual
Name [1] 305703 0
A/Prof Michael Jameson
Address [1] 305703 0
Waikato Cancer and Blood Research Trial Unit
Pembroke Street
Hamilton West
Hamilton 3204
Country [1] 305703 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305669 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 305669 0
Ethics committee country [1] 305669 0
New Zealand
Date submitted for ethics approval [1] 305669 0
02/04/2020
Approval date [1] 305669 0
10/07/2020
Ethics approval number [1] 305669 0
20/NTA/38

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101162 0
Dr Natalie Briggs
Address 101162 0
Cancer and Blood Research Trials Unit
Pembroke Street
Hamilton West
Hamilton 3204
Country 101162 0
New Zealand
Phone 101162 0
+64078398976
Fax 101162 0
Email 101162 0
Oncology_Clinical_Trial@waikatodhb.health.nz
Contact person for public queries
Name 101163 0
Natalie Briggs
Address 101163 0
Cancer and Blood Research Trials Unit
Pembroke Street
Hamilton West
Hamilton 3204
Country 101163 0
New Zealand
Phone 101163 0
+64078398976
Fax 101163 0
Email 101163 0
Oncology_Clinical_Trial@waikatodhb.health.nz
Contact person for scientific queries
Name 101164 0
Natalie Briggs
Address 101164 0
Cancer and Blood Research Trials Unit
Pembroke Street
Hamilton West
Hamilton 3204
Country 101164 0
New Zealand
Phone 101164 0
+64078398976
Fax 101164 0
Email 101164 0
Oncology_Clinical_Trial@waikatodhb.health.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.